A number of prodrugs of the clinically active antiviral agent 9-beta-D-arabinofuranosyladenine (Ara-A), designed to have a greatly increased water-solubility, lipophilicity, and resistance to deamination by adenosine deaminase, have been synthesized and examined for biological activity in preliminary experiments. Some of these prodrugs have been predicted to be much more effective than the parent drug (Ara-A) in penetrating skin based on in vitro diffusion cell experiments. Some derivatives such as the 5'-valerate, the 2',3'-diacetate, and the 3'-proprionate have exhibited significant antiviral activity against herpes simplex virus (HSV) in vitro. In addition, the 2',3'-diacetate derivative of Ara-A has shown promising activity in the topical treatment of HSV type 2 genital infections in guinea pigs. As a result of these preliminary studies and the need for a complete and thorough examination of the therapeutic efficacy of these and other new prodrugs of Ara-A against both local and systemic HSV infections in laboratory animal model systems, this collaborative research program is being proposed for the synthesis of larger amounts of these compounds and their quantitative evaluation against HSV type 1 cutaneous infections in hairless mice, HSV type 2 genital infections in guinea pigs, and HSV type 1-induced encephalitis in mice. We believe that these studies may ultimately lead to the development of topically active Ara-A derivatives for use in the successful treatment of oral and genital herpes virus infections in man.